Human coronaviruses (HCoV) are associated with a range of respiratory illnesses that affect the status of underlying chronic lung diseases and congestive heart failure. In 1998-99, prototype HCoV strains (229E and OC43) were associated with about 1/7th of acute respiratory illnesses in chronically ill veterans. Recently described groups 1 and 2 HCoV strains (NL63 and HKU1) were associated with a small number of illnesses in 1998-99. Re-evaluations of the spectrum of HCoV-associated illness and virulence of new viral strains are needed. This study will prospectively assess the clinical impact of HCoV in older, chronically ill patients compared to healthy young adults. Hypotheses: 1) Acute respiratory illness associated with HCoV infection is clinically significant, results in unplanned utilization of health care services in older, chronically ill patients compared to younger patients and has seasonal and inter-year patterns, 2) Strains of HCoV that are currently circulating are different than in 1998-99 and prototype strains, and are associated with more severe illness, and 3) Spike (S) gene nucleotide sequence variability may contribute to pathogenicity and severity of illness. We propose a four year, prospective clinical trial to assess acute respiratory illnesses in 500 patients aged 60 years and older with chronic lung and heart disease and a comparator group of 500 young healthy adults. We will identify illnesses that are associated with groups 1 and 2 HCoV infection determined by serology and RT- PCR. Nasal washings will be used to assess mucosal antibody responses. Serum neutralizing antibodies will be measured to further assess strain specificity and functionality of the immune response. Nasal/oropharyngeal secretions will be tested for HCoV viral RNA by RT-PCR, and those positive will undergo sequence analysis of the Spike (S) gene that encodes the viral S protein. The S protein appears functionally important, because it is responsible for receptor binding and fusion and is a determinant of virulence and tissue tropism. Consensus sequences of PCR products will be compared to determine diversity of currently circulating viral strains and will be compared to historical and prototype strains. Analysis of the S gene sequences and the clinical illnesses will allow hypothesis generation regarding contributions of sequence to virulence. We will assess clinical signs and symptoms, duration and severity of acute illness, and health care utilization, comparing between the two subject groups and between HCoV strains. Impact on Veterans Health Care: Characterization of HCoV-caused illnesses, currently circulating strains, their seasonal incidence and viral divergence from historical and prototype strains that may be associated with pathogenicity, will improve our knowledge of the impact of HCoV infections on an at-risk VA patient population. Improved care of patients and information to guide future projects focused on the development of antiviral therapy and vaccines are possible benefits. PUBLIC HEALTH RELEVANCE: VA patient populations with underlying heart and lung diseases are susceptible to infection with human coronaviruses (HCoV). The common cold, but also more severe illnesses involving the respiratory tract may result, including those similar to influenza and even pneumonia. The impact of such infections on this population will be assessed in this four year study in terms of frequency in different seasons, the characteristics and severity of the associated illness and resultant use of healthcare resources. Five hundred older patients with underlying chronic lung and heart diseases and 500 younger, healthy adults will be enrolled in the study. Illnesses in the older patients will be compared to those in younger, healthy adults. Understanding the burden of HCoV infection in VA patients and the effects of viral diversity on clinical findings may provide impetus for future studies seeking the development of new antiviral treatments and vaccines. Knowing the seasonal and inter-year changes in the HCoV strains that circulate and the impact of HCoV infections on healthcare utilization will also help in planning for the care of patients and potentially improve healthcare for veterans.